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Ligand-mediated cytoplasmic retention of the Ah receptor inhibits
macrophage-mediated acute inflammatory responses
#MMPMID28892097
Muku GE
; Lahoti TS
; Murray IA
; Podolsky MA
; Smith KJ
; Hubbard TD
; Kuzu G
; Gowda K
; Amin SG
; Perdew GH
Lab Invest
2017[Dec]; 97
(12
): 1471-1487
PMID28892097
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The Ah receptor (AHR) has been shown to exhibit both inflammatory and
anti-inflammatory activity in a context-specific manner. In vivo
macrophage-driven acute inflammation models were utilized here to test whether
the selective Ah receptor modulator
1-allyl-7-trifluoromethyl-1H-indazol-3-yl]-4-methoxyphenol (SGA360) would reduce
inflammation. Exposure to SGA360 was capable of significantly inhibiting
lipopolysaccharide (LPS)-mediated endotoxic shock in a mouse model, both in terms
of lethality and attenuating inflammatory signaling in tissues. Topical exposure
to SGA360 was also able to mitigate joint edema in a monosodium urate (MSU)
crystal gout mouse model. Inhibition was dependent on the expression of the
high-affinity allelic AHR variant in both acute inflammation models. Upon
peritoneal MSU crystal exposure SGA360 pretreatment inhibited neutrophil and
macrophage migration into the peritoneum. RNA-seq analysis revealed that SGA360
attenuated the expression of numerous inflammatory genes and genes known to be
directly regulated by AHR in thioglycolate-elicited primary peritoneal
macrophages treated with LPS. In addition, expression of the high-affinity
allelic AHR variant in cultured macrophages was necessary for SGA360-mediated
repression of inflammatory gene expression. Mechanistic studies revealed that
SGA360 failed to induce nuclear translocation of the AHR and actually enhanced
cytoplasmic localization. LPS treatment of macrophages enhanced the occupancy of
the AHR and p65 to the Ptgs2 promoter, whereas SGA360 attenuated occupancy. AHR
ligand activity was detected in peritoneal exudates isolated from MSU-treated
mice, thus suggesting that the anti-inflammatory activity of SGA360 is mediated
at least in part through AHR antagonism of endogenous agonist activity. These
results underscore an important role of the AHR in participating in acute
inflammatory signaling and warrants further investigations into possible clinical
applications.
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